Adamantane derivatives

ABSTRACT

ADAMANTANE DERIVATIVES HAVING THE FOLLOWING GENERAL FORMULA:   3-(R1-N(-R2)-CH2-CH(-OH)-CH2-O-CH2-)ADAMANTANE   AND THEIR PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS ARE USEFUL AS SYMPATICOLYTIC, MYOLITIC, ANALGESIC AND, PARTICULARLY, AS LOCAL ANAESTHETIC AND B-ADRENERGIC BLOCKING AGENTS. THE NOVEL COMPOUNDS ARE PREPARED STARTING FROM 1 - HYDROXY-METHYL-ADAMANTANE THROUGH THE NEW INTERMEDIATE 1-(ADAMANTYL-METHYLOXY)-2,3-EPOXYPROPANE.

United States Patent C) 3,748,346 ADAMANTANE DERIVATIVES Andrea Pedrazzoli, Milan, and Leone DallAsta, Pavia, Italy, assignors to Societe dEtudes de Recherches et dApplications Scientifiques et Medicales-E.R.S.M.E., Paris, France No Drawing. Original application June 4, 1970, Ser. No. 43,582. Divided and this application Feb. 10, 1972, Ser. No. 225,352

Int. Cl. C0711 1/18 U.S. Cl. 260-348 R 1 Claim ABSTRACT OF THE DISCLOSURE Adamantane derivatives having the following general formula:

and their pharmaceutically acceptable acid addition salts are useful as sympaticolytic, myolitic, analgesic and, particularly, as local anaesthetic and B-adrenergic blocking agents. The novel compounds are prepared starting from 1 hydroxy-methyl-adamantane through the new intermediate l-(adamantyl-methyloxy)-2,3-epoxypropane.

BRIEF SUMMARY OF THE INVENTION This is division of application Ser. No. 43,582, filed June 4, 1970 and now U.S. Patent No. 3, 663,617.

The present invention relates to novel derivatives of adamantane having the following general formula:

wherein R is hydrogen or an aliphatic hydrocarbon radical having up to 8 carbon atoms, R is an aliphatic hydrocarbon radical having up to 8 carbon atoms or a cycloalkyl radical of from 4 to 7 carbon atoms, or R and R are joined to form a pyrrolidino, piperidino, hexamethyleneimino, morpholino, N-lower alkyl piperazino, 2,2,S,5 tetramethyl-pyrrolidino, 2,5 dihydro-2,2,5,5-tetramethylpyrrolino, 2,2,6,6-tetramethyl-piperidino or 1,2,3,6-tetrahydro 2,2,6,6 tetramethyl-pyridino group, R being a cycloalkyl radical only when R is hydrogen, and to pharmaceutically-useful salts of these compounds with inorganic or organic acids.

They have a remarkable pharmacological activity, in particular they are useful as sympathicolytic, myolitic, analgesic, and, particularly, as local anaesthetic and 13- adrenergic blocking agents.

The invention is also concerned with a compound of formula:

useful as an intermediate in the synthesis of the active products.

DETAILED DESCRIPTION The term aliphatic hydrocarbon radical having up to 8 carbon atoms, as used herein, includes straight or branched alkyl and alkenyl radicals having from 1 to 8 3,748,346 Patented July 24, 1973 III where R and R have the meaning defined above.

l-hydroxy-methyl adamantane is reacted with epichlorhydrin in the presence of a catalytic quantity of concentrated sulfuric acid. The reaction is carried out at a temperature of 70-150 (3., preferably C., for a period ranging from 20-60 hours, preferably 45 hours. At the end of the reaction the compound H thus obtained is distilled under high vacuum and then reacted under stirring with powdered anhydrous alkali hydroxide, preferably potassium hydroxide, in anhydrous ethyl ether at room temperature for a time ranging from 10-40 hours, preferably 25 hours.

1 (adamantyl-methyloxy)-2,3-epoxy-propane, III, is obtained by distillation under high vacuum.

1 (adamantyl-methyloxy)-2,3-epoxy-propane, which is a further object of the present invention, is then reacted with the appropriate amine IV in a polar solvent, such as straight or branched, saturated or unsaturated aliphatic alcohols containing 1 to 7 carbon atoms, preferably namyl or n-hexyl alcohol, at a temperature of 50-185 C., preferably l60 C. for a time ranging from 4-30 hours, preferably 15-22 hours. For those amines having a low boiling point, the reaction is efiected in an auto cla-ve. The derivatives of Formula I are isolated in the form of the base, purified by distillation in vacuo, and can be converted into their pharmaceutically acceptable acid addition salts by reaction with the appropriate acid according to methods well known in the art.

Exemplary pharmaceutically acceptable acid addition salts are those formed with acetic, maleic, fumaric, succinic, tartaric, citric, malic, cinnamic, sulfonic, hydrochloric, hydrobromic, hydriodic, sulfuric, phosphoric and nitric acids, the hydrochlorides being particularly preferred.

The compounds of the invention are stable to light and to heat. They have sympathicolytic, myolitic, analgesic and, particularly, local anaesthetic and B-adrenergic blocking activity and can be mixed with known pharmaceutical car r 'iers for the production of pharmaceutical compositions.

PREPARATION 1- (ad amantylmethyloxy) -2-hydroxy-3-chloro-propane A solution of 198 g. of l-(hydroxymethyl)-adamantane, 117 g. of epichlorhydrin and 1.2 ml. of concentrated sulphuric acid was heated at 115 C. for 45 hours. The small fraction which solidified was first distilled off and then the desired product, the boiling point of which is 120- 125 C. at 0.2 mm. Hg was obtained.

EXAMPLE 1 1- (adamantylmethyloxy) -2,3-ep oxy-prop ane A suspension of 162 g. of l-(adamantylmethyloxy)-2- hydroxy-3-chloro-propane, 1300 ml. of ethyl ether and 105 g. of powdered anhydrous KOH was agitated for 20 hours at room temperature. The mixture was filtered through porous glass and then the solvent followed by the product were distilled oil. 119 g. of l-(adamantylmethyloxy)-2,3-epoxy-propane was obtained, the boiling point of which is 125-130 C./2 mm. Hg.

The infrared spectrum in Nujol gave: epoxide band at 846(m.), 1160(f.), 1250(m.) cm.- ether band at 1100(f.) cmr' OH band absent.

EXAMPLE 2 l-(adarnantylmethyloxy)-2-hydroxy-3-isopropylamino-propane A solution of 22 g. of 1-(adamantylmethoxyloxy)-2,3- epoxy-propane, g. of isopropylamine and 30 ml. of methanol was heated in an autoclave at 140 C. for 10 hours.

The autoclave was cooled, the mixture was distilled under vacuum and 21.5 g. of product was obtained having a boiling point of '140145 C./ 0.3 mm. Hg.

EXAMPLE, 3

1-(adamantylmethyloxy)-2-hydroxy-3 (di-sec.butylamino) -propane A solution of 27 g. of 1-(adamantylmethyloxy)-2,3- epoxy-propane, 26 g. of di-secbutylamine and ml. of amyl alcohol was heated at 135C. for 20 hours. The mixture was concentrated and distilled in vacuo and 22 g. of 1 adamantylmethyloxy) 2 hydroxy-3-(di-sec.butylamino)-propane was obtained, the boiling point of which is 160-163 C./0.1 mm. Hg.

EXAMPLE 4 1-(adamantylmethyloxy)-2-hydroxy-3-(2',2',5',5--tetramethylpyrrolidino)-propane A solution of 22 g. of l-(adamantylmethyloxy)-2,3- epoxy-propane, 25 g. of 2,2,5,6-tetramethylpyrrolidine and 40 ml. of n-hexyl alcohol was heated at 155 C. for 18 hours. The mixture was concentrated and distilled in vacuo and 30.5 g. of 1-(adamantylmethyloxy)-2-hydroxy- 3-(2,2,5', '-tetramethylpyrrolidiuo)-propane was obtained, the boiling point of which is 185 C./ 0.3 mm. Hg. The oil dissolved in isopropanol was treated with gaseous hydrogen chloride. The product was crystallised from isopropanol to obtain 28 g. of the hydrochloride in the form of white crystals, the melting point of which is 232- 234 C.

EXAIVI'PLE 5 By operating as described in Examples 2-4 the following compounds are obtained:

1-(adamantylmethyloxy)-2-hydroxy-3-cyclopentylamino-propane, B.P. 180-185" C./O.2 mm. Hg (M.P. of its hydrochloride: 146-148 C.);

1- ad amantylmethyloxy) -2-hydroxy-3-cyclohexylamino-propane, B.P. 193197 C./O.5 mm. Hg

- (M.P. of its hydrochloride: 208-210 C.);

1-(adamantylmethyloxy)-2-hydroxy-3-morpholinopropane, B.P. -170 C./ 0.2 mm. Hg (M.P. of its hydrochloride: 167-168 C.);

1-(adamantylmethyloxy)-2-hyd1-oxy-3-hexamethyleneimino-propane, B.P. 17 0-173 C./0.02 mm. Hg

(M.P. of its hydrochloride: 193-195 C.);

1- ad amantylmethyloxy) -2-hydroxy-3- (4-methylpiperazino)-propane hydrochloride, M.P. 220 C. (dec.);

1-(adarnantylrnethyloxy)-2-hydroxy-3-(2',2,5',5-

tetramethyl-2',5 '-dihydro-pyrrolino -propane, B.P. 184--188 C./O.2 mm. Hg (M.P. of its hydrochloride: 240-242 C.);

1- (adarnantylmethyloxy) -2-hydroxy-3- 2',2',6'-,6'- tetramethylpiperidino) -propane, B.P. -185 C./O.l mm. Hg (M.P. of its hydrochloride: 238-239 C.); and

1-(adamantylmethyloxy)-2-hydroxy-3-(2',2,6,6'-

tetramethyl-1',2,3',6'-tetrahydropyridino)- propane, B.P. 185190 C./0.3 mm. Hg (M.P. of its hydrochloride: 236238 C.).

We claim: '1. i1-(adamantylmethyloxy)-2,3-epoxy-propane.

References Cited UNITED STATES PATENTS 3,536,732 10/ 1970' Borchert et al. 260-348 R NORMA S. MILESTONE, Primary Examiner 

